case report fetal valproate syndrome with limb...

Case ReportFetal Valproate Syndrome with Limb Defects: An IndianCase Report

Manisha Goyal,1 Ashok Gupta,1 Manish Sharma,2 Priyanshu Mathur,3 and Naresh Bansal3

1Rare Disease Clinic, Department of Pediatrics, SMS Medical College and Hospitals, Jaipur, Rajasthan, India2Accident Emergency, Department of Pediatrics, SMS Medical College and Hospitals, Jaipur, Rajasthan, India3Department of Pediatrics, SMS Medical College and Hospitals, Jaipur, Rajasthan, India

Correspondence should be addressed to Manisha Goyal; [email protected]

Received 25 July 2016; Revised 28 September 2016; Accepted 16 October 2016

Academic Editor: Piero Pavone

Copyright © 2016 Manisha Goyal et al.This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Epilepsy is a common disorder and exposure to antiepileptic drugs during pregnancy increases the risk of teratogenicity. OlderAEDs such as valproate and phenobarbital are associated with a higher risk of major malformations in the fetus than newer AEDslike lamotrigine and levetiracetam. Exposure to valproic acid during first trimester can result in fetal valproate syndrome (FVS),comprising typical facial features, developmental delay, and a variety of malformations such as neural tube defects, cardiac andgenitourinary malformations, and limb defects. We are presenting an Indian case of FVS with major limb defects.

1. Introduction

Valproic acid (VPA) is a commonly used drug for the man-agement of epilepsy and certain mood disorders. It is stilla common drug for epilepsy during pregnancy, despiteincreased awareness of its teratogenicity. The teratogeniceffects of VPA were first recognized in 1980 [1]. Exposureto valproic acid during first trimester can result in fetal val-proate syndrome (FVS). It comprises typical facial features(trigonocephaly, epicanthal folds, infraorbital groove, medialdeficiency of eyebrows, broad nasal root, and short nosewith anteverted nares, shallow philtrum, long thin upperlip, and small mouth), developmental delay, and a varietyof malformations such as neural tube defects, cardiac andgenitourinary malformations, and limb defects [2]. A varietyof limb defects have been reported with FVS. Here, we reporta case of FVSwithmajor limbdefects in an Indian boy, born ofan epileptic mother who had taken sodium valproate duringher pregnancy.

2. Case Summary

An eleven-month-old boy came to our genetic clinic withthe complaints of difficulty in breathing. He was second in

birth order of second degree consanguineous couple at termafter normal vaginal delivery with birth weight of 3 kg. Babywas hospitalized for 5 days for delayed cry at birth. Hismother has history of epilepsy and was on sodium valproatesince last 10 years. She had taken 1000mg of valproate intwo divided doses throughout pregnancy. Baby has globaldevelopmental delay as there is no neck holding and nospeech or interaction with parents at 11 months of age. Hisweight, length, and head circumference were 5 kg (less than3rd centile), 67 cm (less than 3rd centile), and 40.2 cm (lessthan 3rd centile), respectively. Facial examination revealedbifrontal prominence, high forehead, left epicanthal fold,depressed and broad nasal bridge, upturned nares, prominentphiltrum, thin upper lip, posterior cleft palate, and bilaterallow set ears (Figure 1). Limb examination detected shorteningof left forearm, absent thumb, ulnar deviation at wrist andcontracture of 1st, 2nd, and 3rd fingers at PIP joints ofleft hand (Figure 2), and rudimentary thumb with contrac-ture at proximal phalangeal joint of fingers of right hand.Overriding of toes was present on right foot. There was nohepatosplenomegaly norwere there any neurocutaneous stig-mata. Genital examination showed absent testis on left side.His body tone was normal with normal reflexes. X-ray handswere detected with absent radius and with absent thumb

Hindawi Publishing CorporationCase Reports in PediatricsVolume 2016, Article ID 3495910, 4 pageshttp://dx.doi.org/10.1155/2016/3495910

2 Case Reports in Pediatrics

Figure 1: Facial features show bifrontal prominence, high forehead,left epicanthal fold, depressed and broad nasal bridge, upturnednares, prominent philtrum, thin upper lip, and bilateral low set ears.

Figure 2: Left upper limb, short left forearm, absent thumb, ulnardeviation at wrist, and contracture of fingers at PIP joint.

bone on left side (Figure 3). Complete blood counts, renalfunction tests, liver function test, and hearing evaluationwerenormal. Ultrasonography abdomen showed presence of lefttestis in inguinal canal. 2D echocardiography was suggestiveof ostium secundum atrial septal defects of 1.6mm size.A diagnosis of fetal valproate syndrome was made on thebasis of antenatal history of valproate intake, facial dysmor-phism, radial ray defect, cardiac defect, and associated genitalanomaly.

3. Discussion

Epilepsy is a common disorder and exposure to antiepilepticdrugs during pregnancy increases the risk of teratogenicity.The absolute risk of major malformations in infants exposedto antiepileptic drugs is quoted as 7–10% as compared to

Figure 3: X-rays left hand: absent radius with absent thumb bone.

2-3% rate of major malformations in the general popula-tion [3]. The risk is dependent on dose and duration ofdrug and exposure to single drug or multidrug. Study byTomson et al. suggested that the risk of major congenitalmalformations is influenced not only by type of antiepilepticdrug but also by dose and other variables. They assessedrates of major congenital malformations in 1402 pregnanciesexposed to carbamazepine, 1280 on lamotrigine, 1010 onvalproic acid, and 217 on phenobarbital. They concluded thatlamotrigine (less than 300mg per day) and carbamazepine(less than 400mg per day) are associated with lowest ratesof malformation. They found higher risk with valproic acidand phenobarbital as compared with other antiepilepticdrugs [4]. UK epilepsy and pregnancy registry has publishedtheir fifteen-year prospective observational data of intrauter-ine exposure to valproate, carbamazepine, and lamotrigine.They reported that in utero exposure to valproate carriesa significantly higher malformation risk than lamotrigineand carbamazepine monotherapy [5]. Similar observationis reported by North American AED pregnancy registry(Hernandez-Dıaz et al.) as traditional AEDs such as valproateand phenobarbital are associated with a higher risk of majormalformations in the fetus than newer AEDs like lamotrigineand levetiracetam [6].

Study by Morrow et al. showed that those exposed tomore than 1000mg of valproate had the highest risk ofmajor deformities compared to other monotherapy drugs.Carbamazepine had the lowest risk of malformation asmonotherapy drug. The risk is higher for polytherapy thanfor monotherapy. Polytherapy regimens containing valproatehad a higher risk of malformation [7]. In our case motherwas taking 1000mg sodium valproic acid per day since last 10years before conception and continued taking the same dosethroughout pregnancy.

The mechanism(s) to produce teratogenicity by a specificantiepileptic drug remains undiagnosed. Some animal stud-ies using inbred strains ofmice suggested genetic backgroundfor the risk of teratogenicity [8]. Study by Dean et al.showed that the malformations found in fetal anticonvulsant

Case Reports in Pediatrics 3

syndromes are associated with folic acid deficiency andmethylene-tetrahydrofolate reductase (MTHFR) polymor-phisms. They concluded that the risk is three to four timeshigher for mothers who were MTHFR 677TT homozygotescompared with MTHFR 677CC homozygotes [9].

The “fetal valproate syndrome” includes facial dysmor-phism such as epicanthal folds, flat nasal bridge, small nosewith anteverted nares, thin and long upper lip with rela-tively shallow philtrum, and small mouth. Major congenitalmalformations include limb defects, neural tube defects,congenital heart defects, oral clefts, and urogenital abnormal-ities. Other less frequent abnormalities include inguinal andumbilical hernia, supernumerary nipple, low birth weight,behavioral issues, and development delay [10]. Schorry etal. concluded in their study that FVS is associated withearly motor and speech developmental delays, low normalor borderline IQ, and adaptive behaviors [11]. Meador etal. did a prospective multicenter study of cognitive effectsof fetal exposure to commonly used antiepileptic drugs(carbamazepine, lamotrigine, phenytoin, or valproate) inchildren aged 3 years and 4.5 years. They found that childrenwith fetal exposure to valproate had reduced IQ at 6 yearscompared with other commonly used antiepileptic drugs.Valproate exposure was also associated with worse verbal andmemory abilities comparedwith the other antiepileptic drugsand worsened nonverbal and executive functions comparedwith lamotrigine [12].

The risk of a limb abnormality from VPA exposure hasbeen estimated to be about 0.42% [9]. A variety of limbdefects are reported in FVS including preaxial and postaxialpolydactyly, clinodactyly, talipes, broad big toes and finger-like thumbs, contractures of the fingers, arachnodactyly, over-lapping digits and syndactyly, radial ray aplasia or reduction,and phocomelia [13, 14]. In our case radial ray defect waspresent in the form of unilateral absence of radius and thumbalongwith rudimentary thumb on contralateral side. Sharonyet al. showed that the upper extremities are more severelyand frequently affected than the lower extremities in FVS[15]. They also concluded that the extent and severity oflimb reduction defects can also vary from oligodactyly tototal absence of upper extremity. Bilateral deficiency of upperextremities is reported by Guven et al. [14]. Genitourinaryanomalies are seen relatively frequently with VPA exposureincluding hypospadias, undescended testes, renal hypoplasia,hydronephrosis, and duplication of the calyceal system [3, 16].Our patient had unilateral testis. Other genital examinationswere normal and no renal abnormalities were detected on theultrasound scan.

Our case has radial ray defect in view of absent radiuswith absent thumb. Radial ray defect is a large spectrumof anomalies which ranges from partial (radial hypopla-sia) to a complete (radial aplasia) deficiency of the radiuswith or without anomalies of thumb. Differential diagnosesof radial ray defects are Holt-Oram syndrome (cardiac-limb syndrome), Fanconi pancytopenia syndrome, Nageracrofacial dysostosis, thrombocytopenia-absent radius (TARsyndrome), VACTERL syndrome, Baller-Gerold syndrome,Rothmund-Thomson syndrome, Aase syndrome, Townes-Brocks syndrome, and Trisomy 13/18. In our patient blood

counts for all three cell lines were normal, excluding Fan-coni anemia, Aase syndrome, and TAR syndrome. Nor-mal ears/hearing evaluation ruled out Holt-Oram, Townes-Brocks, and Nager syndromes. Absence of other charac-teristic malformations rules out VATER/VACTERL. Patientwas not affording so a sample could not be sent for moreelaborative genetic study such as array CGH or whole exomesequencing.

Management of FVS includes multidisciplinary teamapproach comprising management of the associated malfor-mations. Physiotherapy and early speech therapy are essentialfor patients with developmental delay.

VPA is a widely used AED, particularly in poor resourcecountries like India, and its efficacy cannot be disputed. Thebalance between its therapeutic benefits and its teratogeniceffects is mainstay in the management of pregnant womenwith epilepsy. VPA should not be routinely prescribed. Ifthere is no effective alternative, then doses should be reducedto below 1 gram per day, administered in divided doses andin the slow release form. Also, women who take more thanonemedication for control of their epilepsy should be advisedto change to monotherapy if possible. In addition, high dosefolic acid (5mg/day) should be given to all pregnant womenwith antiepileptic drugs, starting at least 6 weeks beforeconception and continuing through the first trimester [17].

We conclude that pregnant women on antiepileptic drugsare at increased risk formajor congenitalmalformation.Mostof these anomalies can be detected by detailed ultrasoundexamination. So we recommend avoidance of valproic acidif possible, supplementation with folic acid, and a detailedultrasound to these women.

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

References

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[2] H. H. Ardinger, J. F. Atkin, R. D. Blackston et al., “Verificationof the fetal valproate syndrome phenotype,” American Journalof Medical Genetics, vol. 29, no. 1, pp. 171–185, 1988.

[3] J. Jentink, M. A. Loane, H. Dolk et al., “Valproic acidmonother-apy in pregnancy and major congenital malformations,” TheNewEngland Journal ofMedicine, vol. 362, no. 23, pp. 2185–2193,2010.

[4] T. Tomson,D. Battino, E. Bonizzoni et al., “Dose-dependent riskof malformations with antiepileptic drugs: an analysis of datafrom the EURAP epilepsy and pregnancy registry,” The LancetNeurology, vol. 10, no. 7, pp. 609–617, 2011.

[5] E.Campbell, F. Kennedy,A. Russell et al., “Malformation risks ofantiepileptic drugmonotherapies in pregnancy: updated resultsfrom the UK and Ireland epilepsy and pregnancy registers,”Journal of Neurology, Neurosurgery & Psychiatry, vol. 85, no. 9,pp. 1029–1034, 2014.

4 Case Reports in Pediatrics

[6] S. Hernandez-Dıaz, C. R. Smith, A. Shen et al., “Comparativesafety of antiepileptic drugs during pregnancy,” Neurology, vol.78, no. 21, pp. 1692–1699, 2012.

[7] J. Morrow, A. Russell, E. Guthrie et al., “Malformation risksof antiepileptic drugs in pregnancy: a prospective study fromthe UK Epilepsy and Pregnancy Register,” Journal of Neurology,Neurosurgery & Psychiatry, vol. 77, no. 2, pp. 193–198, 2006.

[8] A. Faiella, M.Wernig, G. G. Consalez et al., “Amousemodel forvalproate teratogenicity: parental effects, homeotic transforma-tions, and alteredHOX expression,”HumanMolecular Genetics,vol. 9, no. 2, pp. 227–236, 2000.

[9] J. Dean, Z. Robertson, V. Reid et al., “Fetal anticonvulsant syn-dromes and polymorphisms in MTHFR, MTR, and MTRR,”American Journal of Medical Genetics, Part A, vol. 143, no. 19,pp. 2303–2311, 2007.

[10] K. L. Jones, Smith’s Recognizable Patterns of Human Malfor-mation, WB Saunders Company, Philadelphia, Pa, USA, 5thedition, 1997.

[11] E. K. Schorry, S. G. Oppenheimer, and H. M. Saal, “Valproateembryopathy: clinical and cognitive profile in 5 siblings,”American Journal of Medical Genetics, vol. 133, no. 2, pp. 202–206, 2005.

[12] K. J.Meador, G. A. Baker, N. Browning et al., “Fetal antiepilepticdrug exposure and cognitive outcomes at age 6 years (NEADstudy): a prospective observational study,” The Lancet Neurol-ogy, vol. 12, no. 3, pp. 244–252, 2013.

[13] E. Rodrıguez-Pinilla, I. Arroyo, J. Fondevilla, M. J. Garcıa,and M. L. Martınez-Frıas, “Prenatal exposure to valproic acidduring pregnancy and limb deficiencies: a case-control study,”American Journal of Medical Genetics, vol. 90, no. 5, pp. 376–381, 2000.

[14] M.A. Guven, C. Batukan, S. Ceylaner, G. Ceylaner, andM.Uzel,“A case of fetal anticonvulsant syndrome with severe bilateralupper limb defect,” Journal of Maternal-Fetal and NeonatalMedicine, vol. 19, no. 2, pp. 115–117, 2006.

[15] R. Sharony, A. Garber, D. Viskochil et al., “Preaxial ray reduc-tion defects as part of valproic acid embryofetopathy,” PrenatalDiagnosis, vol. 13, no. 10, pp. 909–918, 1993.

[16] E. Jager-Roman, A. Deichl, S. Jakob et al., “Fetal growth, majormalformations, andminor anomalies in infants born to womenreceiving valproic acid,”The Journal of Pediatrics, vol. 108, no. 6,pp. 997–1004, 1986.

[17] P. Crawford, R. Appleton, T. Betts et al., “The women withepilepsy guidelines development group. Best practice guidelinesfor themanagement of womenwith epilepsy,” Seizure, vol. 8, no.4, pp. 201–217, 1999.

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